Inhibitors of SRS-synthesis

ABSTRACT

Methyl derivatives of arachidonic acid and intermediates thereto have been synthesized. These derivatives are inhibitors of SRS-A synthesis and are useful for treating and preventing allergic reactions.

BACKGROUND OF THE INVENTION

In mammals, essential fatty acids such as arachidonic acid serve assubstrates for cellular biological processes producing prostaglandinsand the material SRS-A (Slow Reacting Substance of Anaphylaxis), thepathway to prostaglandins being catalyzed by prostaglandin synthetaseand the pathway to SRS-A being catalyzed by lipoxygenase. Theprostaglandin pathway leads to products of known beneficial function inmammals, while the SRS-A pathway produces products which have no knownbeneficial function in mammals.

After its cellular biosynthesis SRS-A is released from the cell oforigin and produces effects such as bronchoconstriction during anallergic response. There has been an ongoing need for agents that willspecifically inhibit the synthesis of SRS-A by mammalian cells in orderto prevent the release of SRS-A and the resulting asthmatic conditionsthereto. In the past, methyl derivatives of arachidonic acid have beenprepared. These derivatives relate to the inhibition of prostaglandinsynthesis in order to treat disorders apparently arising therefrom.

In particular arachidonic acids methylated in the 2 or 3 position of thechain have been made by classical procedures wherein the intactarachidonic acid compound is methylated [Liang et al., Adv. Prost.Thrombox. Res. 6, 235 (1980)]. Also arachidonic acid analogs methylatedin the 13 position have been disclosed by Yeh and Dawson, TetrahedronLetters No. 49, pp 4257-4260, (1977). This disclosure relates tocompounds which have potential prostaglandin synthetase inhibitoryactivity.

SUMMARY OF THE INVENTION

In accordance with this invention, compounds are provided which inhibitthe synthesis of SRS-A without inhibiting the synthesis ofprostaglandins. The compounds of this invention are compounds of theformula ##STR1## wherein Δ designates cis configuration across a doublebond; the dotted lines designate optionally a double bond or ahydrognated bond; R represents hydrogen or lower alkyl; and R₁ and R₂represent hydrogen or methyl with the proviso that where one of R₁ andR₂ is hydrogen the other is methyl; and pharmaceutically acceptable baseaddition salts thereof when R is hydrogen.

The compounds of formula XII are prepared from novel intermediates ofthe formula ##STR2## wherein Δ, the dotted lines, R, R₁ and R₂ are asdefined earlier; R₃ represents hydrogen or an ether protecting group; R₄represents --CH₂ OH or --CHO; R' represents lower alkyl and R"represents a phosphonium salt whereby a compound of formula IV isconverted to a compound of formula VI which is treated with a compoundof formula X to produce a compound of formula XII.

The compounds of formulas IV, VI, X and XII are produced such that thestereo configuration about a carbon-carbon double bond is cis.

The compounds of formula XII have been discovered to be potentinhibitors of SRS-A synthesis and therefore are useful as anti-allergicagents or anti-asthmatic agents; while compounds of formulas IV, VI andX have been discovered to be useful in producing compounds of formulaXII. The compounds of formula XII are specific inhibitors of SRS-Aproduction, but such compounds do not significantly affect thebiosynthesis of prostaglandins.

DETAILED DESCRIPTION OF INVENTION

The term "lower alkyl" comprehends both straight and branched chainsaturated hydrocarbon groups having 1 to 7 carbon atoms, such as methyl,ethyl, propyl, isopropyl and the like.

The term "phosphonium salt" comprehends any phosphonium salt capable offorming a cis carbon-carbon double bond when such salt is condensed in aWittig reaction with an aldehyde in the presence of a strong base. Amongsuch phosphonium salts there are especially included thetriaryl-phosphonium halides such as triphenyl or tritolylphosphoniumhalides. The triphenylphosphonium halide is preferred. Strong baseswhich may be employed in the Wittig reaction include such bases as loweralkyl-or aryllithium reagents such as phenyllithium, methyllithium,n-butyllithium and the like, wherein n-butyllithium is preferred.

The term "halide" comprehends conventionally compounds containing ahalogen which is inclusive of such atoms as bromine, chlorine, fluorineand iodine.

The term "ether protecting group" comprehends a hydrolyzable ether groupremovable by conventional hydrolysis or acid catalyzed cleavage. Anyconventional ether group that may be hydrolyzed or cleaved by acid toyield a hydroxy group can be utilized as the ether protecting group. Forexample ether protecting groups useful for the purpose of this inventioninclude tetrahydropyranyl ethers, ethoxyethylethers, methoxy isopropylethers, and aryl or aryl lower alkyl ethers such as benzhydryl, trityland the like.

Acid catalyzed cleavage of the ether protecting group may be carried outby conventional treatment with a strong organic or inorganic acid. Amongthe organic acids there are included lower alkanoic acids, i.e. acidshaving 2 to 7 carbon atoms, such as acetic acid, propionic acid, and thelike. Inorganic acids are preferred. Among the preferred inorganic acidsare the mineral acids such as sulfuric acid, hydrochloric acid and thelike. In carrying out this reaction, temperature and pressure are notcritical and this reaction may be carried out at room temperature andatmospheric pressure.

The term "cis" represented by Δ designates the fact that the two largestgroups attached across a carbon-carbon double bond are on the same sideof such double bond.

The compounds of formula XII can be used in accordance with thisinvention in their salt form. Any conventional pharmaceuticallyacceptable base addition salts of the compounds of formula XII may beutilized. Pharmaceutically acceptable base addition salts include anyconventional non-toxic salt such as the sodium salt, potassium salt,ammonium salt and the like, formed by neutralization of the acid form ofcompounds of formula XII with an alkaline metal hydroxide or ammoniumhydroxide.

The processes of the present invention relate to processes by which thecis configuration of the olefinic bonds in compounds of formula XII areformed. These processes are summarized in the following reaction schemesI, II and III. For such reactions, temperature and pressure of theresulting reaction mixture are not critical, unless otherwise noted, androom temperature and atmospheric pressure are suitable for carrying outthese reactions, as well as elevated or reduced temperatures andpressures. Where it is noted that a reaction is carried out under aninert atmosphere, any conventional inert gas can be utilized in aconventional manner to create the inert atmosphere. Generally such inertgases include for example argon, nitrogen, or helium. A critical featureof each reaction is such that any resulting carbon-carbon double bondformed in a reaction product occurs in or be maintained in the cisconfiguration.

Reaction Scheme I ##STR3## wherein Δ, R', R₁, R₂ and R₃ are as definedearlier. Reaction Scheme II ##STR4## wherein Δ, the dotted lines and R"are as defined earlier; R₁₀ represents lower alkyl or aryl sulfonyl; andR'" represents a halide. Reaction Scheme III ##STR5## wherein Δ, thedotted lines, R₁, R₂ and R' are as defined earlier. Step A

In step A of reaction scheme I, the starting compounds are the compoundsof formula I and II which are reacted via a Wittig reaction in aconventional manner to produce the compound of formula III. The weightratio of compound of formula I to the compound of formula II is notcritical but it is preferred that the compound of formula II be instoichiometric excess to the compound of formula I. This reaction ofstep A is a condensation reaction between an aldehyde, e.g. a compoundof formula I and a phosphonium halide salt, e.g. the compound of formulaII in a cis-stereoselective Wittig reaction. This reaction is generallycarried out using a deprotonating agent such as an alkyl or aryl lithiumbase such as n-butyllithium in an ether solvent such as tetrahydrofuranand a co-solvent of tetramethylethylenediamine orhexamethylphosphorictriamide. Temperature and pressure for this reactionare not critical but it is preferred that the reaction be carried outbetween -30° C. and room temperature at atmospheric pressure.

It is an essential feature of this reaction step that the resultingcarbon-carbon double bond formed in the reaction product, i.e., thecompound of formula III, be in the cis configuration. Any of theconventional conditions used for producing such a cis configuration by aWittig reaction can be used to carry out this step.

More particularly for example a compound of formula I such as thecompound of formula ##STR6## may be reacted via Wittig reaction with acompound of formula II to produce a compound of formula III such as thecompound of formula ##STR7## wherein Δ is a described earlier.

Step B

A compound of formula III is converted to a compound of formula IV inStep B of Reaction Scheme I by esterification. The compound of formulaIII can be esterified by any conventional means using any conventionalesterifying agent such as diazomethane or a lower alkyl halide. The cisconfiguration of the carbon-carbon double bond in the compound offormula III will be maintained in the compound of formula IV' under theconventional conditions for esterification.

More particularly for example a compound of formula III such as thecompound of formula III' may be esterified conventionally by theesterifying agent CH₂ N₂ to provide the compound of formula ##STR8##wherein Δ is as described earlier.

Step C

A compound of formula IV' is converted to a compound of formula V inStep C of reaction Scheme I by hydrolysis of the ether bond formed by R₃(an ether protecting group) to yield a hydroxy group in the compound offormula V. This hydrolysis reaction may be carried out as describedearlier utilizing conventional hydrolysis or an acid catalyzed cleavagereaction of the ether protecting group.

More particularly for example a compound of formula IV' such as thecompound of formula IV" may be hydrolyzed by an acid such as dilutehydrochloric acid to provide by the acid catalyzed cleavage the compoundof formula ##STR9## wherein Δ is as described earlier.

Step D

The compound of formula V is converted to the compound of formula VI' inStep D of Reaction Scheme I by treating the compound of formula V withan oxidizing agent. Any conventional oxidizing agent which may beutilized to convert a primary alcohol to an aldehyde can be used. Amongthe preferred oxidizing agents are included chromium trioxide dipyridinecomplex, pyridinium dichromate, and the like. Any of the conditionsconventionally utilized with these oxidizing agents can be utilized inthis conversion.

The compound of formula VI' resulting from the reaction of Step D ofReaction Scheme I is employed in Step H of the reactions of ReactionScheme III.

More particularly for example a compound of formula V such as thecompound of formula V' may be oxidized by treatment with a chromateoxidizing agent to provide the compound of formula ##STR10## wherein Δis as described earlier.

Step E

In Step E of reaction Scheme II, a compound of formula VII is activatedby reacting such compound with a sulfonating agent to provide a compoundof formula VIII. Any agent such as a lower alkyl or aryl sulfonyl halidewhich will react with the hydroxy group of the compound of formula VIIto provde another group, i.e. an activated group for introducing ahalide, may be used as the sulfonating agent. Among such agents areincluded for example such compounds as methanesulfonyl chloride,benzenesulfonyl chloride, p-toluenesulfonyl chloride (p-TsCl) and thelike. Step E of reaction Scheme II may be by-passed to Step F whereinthe compound of formula VII is halogenated conventionally by ahalogenating agent to provide the compound of formula IX. For such aby-pass, any of the conventional conditions for halogenating an alcoholvia any conventional halogenating agent may be used to carry out areaction of converting a compound of formula VII to a compound offormula IX. It is preferred, however, that Step E be performed in orderto achieve a high yield in the halogenation process.

Step F

A compound of formula VIII is halogenated in Step F to provide acompound of formula IX. The halogenation will replace the activatedgroup of the compound of formula VIII with a halogen from a halogenatingagent. The halogenating agent may be a halogen or salt thereof such asfor example an alkali metal halide such as NaI, LiI, KI, CsI and thelike.

More particularly for example a compound of formula VIII may be reactedwith a halogenating agent such as NaI conventionally to provide thecompound of formula ##STR11## wherein Δ and the dotted lines are aspreviously described.

Step G

A compound of formula IX is converted to the compound of formula X inStep G by treating the compound of formula IX with a phosphine. Anyphosphine which will react with a compound of formula IX to provide aphosphonium halide capable of condensation in a Wittig reaction with acompound of formula VI' to provide thereby the formation of a ciscarbon-carbon double bond may be utilized as the phosphine. Among suchphosphines are included for example the triarylphosphines such astriphenylphosphine and tritolylphosphine.

More particularly for example a compound of formula IX such as thecompound of formula IX' may be reacted with a phosphine such astriphenyl phosphine to provide the compound of formula ##STR12## whereinΔ and the dotted lines are as previously described.

Step H and I

In Step H of reaction Scheme III, a compound of formula VI' is treatedwith a compound of formula X in the presence of a strong base (such asthe lower alkyl or aryllithium reagents previously referred to) toproduce the compound of formula XI, utilizing a Wittig reaction. Any ofthe conditions conventional in condensing an aldehyde and a phosphoniumsalt, which permits formation of a cis carbon-carbon double bond, may beemployed. Generally this reaction is initiated at low temperatures suchas at a temperature of about -40° under an inert atmospheric pressure,and then brought to room temperature for conventional extraction ofproduct after the reaction between the compound of formula VI' andformula X has been completed.

The compound of formula XI may be converted to the corresponding acid, acompound of formula XII, by any conventional saponification orhydrolysis or dealkylation reaction. For example saponification orhydrolysis may be effected by treating a compound of formula XI with analkaline metal hydroxide such as NaOH, KOH, LiOH or the like at roomtemperature. While, for example, dealkylation may be effected bytreating a compound of formula XI with an alkaline metal halide such asLiI, KI, CsI or the like in a pyridine solvent. Suitable pyridinesolvents include pyridine and methylated pyridines such as collidine,lutidine and the like. It is preferred that dealkylation be carried outusing lithium iodide in a pyridine solvent.

More particularly for example a compound of formula VI' such as thecompound of formula VI" may be condensed with a compound of formula Xsuch as the compound of formula X' to provide the compound of formula##STR13## wherein Δ and the dotted lines are as previously defined.

The compound of formula XI' then can be converted by conventionalhydrolysis to a compound of formula ##STR14## wherein Δ and the dottedlines are as previously defined.

The novel compounds of formula XII are potent inhibitors of SRS-Abiosynthesis and therefore are useful as anti-allergic agents oranti-asthmatic agents; while compounds of formula IV, VI, and X areuseful as intermediates in producing compounds of formula XII as byprocesses described above.

Prophylactically effective amounts of a compound of formula XII, saltsor esters thereof or pharmaceutical compositions containingprophylactically effective amounts of these compounds can beadministered by methods well known in the art. Thus they can beadministered, either singly or with other pharmaceutical agents, e.g.,antagonists of mediators of anaphylaxis such as antihistamines, oranti-asthmatic steroids such as prednisone and prednisolone, orally,parenterally or by inhalation, e.g., in the form of an aerosol,micropulverized powder or nebulized solution. For oral administrationthey can be administered in the form of pills, tablets, capsules, e.g.,in admixture with talc, starch, milk sugar or other inert ingredients,i.e. pharmaceutically acceptable carriers, or in the form of aqueoussolutions, suspensions, encapsulated suspensions, gels, elixirs oraqueous alcoholic solutions, e.g., in admixture with sugar or othersweetening agents, flavorings, colorants, thickeners and otherconventional pharmaceutical excipients. For parenteral administration,they can be administered in solutions or suspension, e.g., as an aqueousor peanut oil solution or suspension using excipients and carriersconventional for this mode of administration. For administration asaerosols, they can be dissolved in a suitable pharmaceuticallyacceptable solvent, e.g., ethyl alcohol or water or combinations ofmiscible solvents, and mixed with a pharmaceutically acceptablepropellant. Such aerosol compositions are packaged for use in apressurized container fitted with an aerosol valve suitable for releaseof the pressurized composition. Preferably, the aerosol valve is ametered valve, i.e., one, which on activation, releases a predeterminedeffective dose of the aerosol composition.

In practicing the method of the invention, the dose of compound offormula XII or salts or esters thereof to be administered and thefrequency of administration will be dependent on the potency andduration of activity of the particular compound to be administered andon the route of administration, as well as the severity of thecondition, age of the mammal to be treated, etc. Doses of compound offormula XII contemplated for use in practicing the method of theinvention are about 0.01 to be 100 mg per kilogram of body weight perday, preferably about 0.1 to about 10 mg per kilogram of body weight perday, either as a single dose or in divided doses.

The following examples are further illustrative of the invention but arenot meant to restrict the invention in scope or spirit.

EXAMPLE I

To a suspension of 4.43 g (10 mmols) of(4-carboxybutyl)triphenylphosphonium bromide in 20 ml ofhexamethylphosphorictriamide and 28 ml of tetrahydrofuran was addeddropwise at 0°-5° C., and under argon, 12 ml of 1.6 M butyllithium inhexane. The reaction mixture turned deep red in color. After stirringfor 1 hr. at room temperature, 1.08 g (5.86 mmoles) of2,2-dimethyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]propanal (H. Marschall, etal., Chem. Ber. 107, 887 (1974)) in 3 ml of tetrahydrofuran was added.The resulting mixture was stirred for 17 hrs. at room temperature andthen diluted with brine and extracted with hexane. The aqueous phase wasacidified with a saturated solution of oxalic acid and extracted fourtimes with ether. The ether extracts were combined, dried over anhydrousmagnesium sulfate, filtered, and the solvent was removed in vacuo toyield 2.4 g of crude(Z)-7,7-dimethyl-8-[(tetrahydro-2H-pyran-2-yl)oxy]-5-octenoic acid whichwas subsequently converted into the methyl ester derivative by treatmentwith a freshly prepared ethereal solution of diazomethane. The crudeester (2.35 g), obtained after removal of the solvent, waschromatographed on a silica gel column. A mixture of hexane-ether (7:3)eluted 1.24 g (75.2%) of(Z)-7,7-dimethyl-8-[(tetrahydro-2H-pyran-2-yl)oxy]-5-octenoic acidmethyl ester. This material was dissolved in 15 ml of methanol andtreated with 0.5 ml of 2 N hydrochloric acid. The mixture was stirredfor 3 hrs. at room temperature. Ca. 10 ml of methanol was evaporated invacuo. The remaining solution was diluted with ether and poured into asaturated solution of sodium bicarbonate. The organic layer was washedwith brine, dried (MgSO₄), and concentrated under reduced pressure toyield 0.940 g of crude material. Chromatographic purification of theproduct on a silica gel column yielded 0.610 g (69.8%) of pure(Z)-8-Hydroxy-7,7-dimethyl-5-octenoic acid methyl ester (98.9% pure, byGC).

Anal. Calcd. for C₁₁ H₂₀ O₃ : C, 65.97; H, 10.07. Found: C, 66.03; H,9.85.

EXAMPLE II

0.530 g (2.65 mmoles) of (Z)-8-Hydroxy-7,7-dimethyl-5-octenoic acidmethyl ester in 5 ml of methylene chloride was added slowly to a mixtureof CrO₃ (2.1 g; 21 mmol) and pyridine (3.5 g; 42 mmol) suspended in 55ml of methylene chloride at room temperature. The reaction mixture wasstirred for 5 hrs. The dichloromethane phase was decanted, and theprecipitate was washed three times with ether. The organic phases werecombined, washed with chilled 1 N sodium hydroxide, 1 N sulfuric acid,saturated sodium bicarbonate solution and brine then dried (MgSO₄) andconcentrated to give 0.53 g of crude material. Purification bychromatography or a silica gel column afforded 0.405 g (77.1%) of pure(Z)-8-Oxo-7,7-dimethyl-5-octenoic acid methyl ester (100% pure, byGC-analysis).

Anal. Calcd. for C₁₁ H₁₈ O₃ : C, 66.64; H, 9.15. Found: C, 66.94; H,9.14.

EXAMPLE III

To a solution of 8.7 g (45 mmoles) of p-toluenesulfonyl chloride in 60ml pyridine was added dropwise at 0°-5° C., a solution of 5.8 g (31.8mmoles) of (Z,Z)-3,6-dodecadienol (T. Kajiwara, J. Sekiya, Y. Odake andA. Hatanaka, Agric. Biol. Chem., 41, 1481 (1977)). The temperature wasallowed to rise to 25° C., and the reaction mixture was stirred at roomtemperature overnight. The resulting suspension was slowly poured into amixture of 1 N aqueous sulfuric acid and ice and the product extractedwith ether. The ether extracts were combined, washed with 10% sodiumchloride solution, dried over anhydrous magnesium sulfate, and thesolvent evaporated under reduced pressure. The residue (8.0 g) waschromatographed on a silica gel column. Elution with 1:1 hexane-ethergave 4.9 g (14.6 mmoles) (45.8%) of (Z,Z)-3,6-dodecadienyl tosylate,which was dissolved in 20 ml of acetone.

This solution was added at 0°-5° C. to a solution of 9.8 g (65 mmoles)of NaI in 90 ml of acetone. After stirring at room temperature for 17hrs., most of the acetone (ca. 70 ml) was removed in vacuo. The residuewas diluted with hexane and poured into 10% sodium bisulfite solution.The hexane solution was washed twice with water, dried (MgSO₄), andevaporated under reduced pressure. The residue (4.19 g) wasevaporatively distilled to give 4.1 g (96.2%) of(Z,Z)-1-iodo-3,6-dodecadiene. (90.2% pure by GC).

Anal. Calcd. for C₁₂ H₂₁ I: C, 49.33; H, 7.24 Found: C, 49.00; H, 7.23.

EXAMPLE IV

A mixture of (Z,Z)-1-iodo-3,6-dodecadiene (1.02 g; 3.49 mmoles) andtriphenylphosphine (0.90 g; 3.41 mmoles) was heated at 90° C., underargon, for 2 hrs. The resultant glassy phosphonium salt (1.90 g) wasused without purification.

EXAMPLE V

To a solution of 1.50 g (2.7 mmoles) of(Z,Z)-3,6-dodecadienyl(triphenyl)phosphonium iodide in 2.5 ml ofhexamethylphosphorictriamide and 4 ml of tetrahydrofuran, under argon,was added at -40° C., 1.4 ml of a 1.6 M solution of n-butyllithium inhexane, by a syringe. Then 0.360 g (1.82 mmoles) of(Z)-8-oxo-7,7-dimethyl-5-octenoic acid methyl ester in 1 ml oftetrahydrofuran was immediately added to the reaction mixture. Theresulting mixture was stirred for 20 min. at -40° C., then thetemperature was allowed to rise to room temperature. After two hours,the reaction mixture was poured into saturated ammonium chloridesolution and extracted with hexane. The organic phase was washed twicewith brine, dried over anhydrous magnesium sulfate, and the solvent wasremoved in vacuo. The crude material so obtained (0.93 g) waschromatographed on a silica gel column. Hexane-ether (1:1) eluted 0.604g (95%) of (all Z)-7,7-dimethyleicosa-5,8,11,14-tetraenoic acid methylester (86.4% pure by GC analysis).

Anal. Calcd. for C₂₃ H₃₈ O₂ : C, 79.71; H, 11.05. Found: C, 79.48; H,10.95.

EXAMPLE VI

A mixture of (all-Z)-7,7-dimethyleicosa-5,8,11,14-tetraenoic acid methylester (0.130 g; 0.37 mmoles), and lithium iodide (0.420 g; 3.13 mmoles)in 3 ml of pyridine was heated at 120°-125° C. for 24 hrs. The mixturewas poured into brine, acidified with 2 N HCl and extracted with ether.The etheral extract was dried and the solvent removed in vacuo. Theresidue (0.105 g) was chromatographed on a silica gel column to give 98mg (78.5%) of pure (all-Z)-7,7-dimethyleicosa-5,8,11,14-tetraenoic acid.(>99% pure by GC analysis).

Anal. Calcd. for C₂₂ H₃₆ O₂ : C, 79.46; H, 10.91. Found: C, 79.02; H,10.71.

EXAMPLE VII

To a solution of 3.20 g (17.5 mmoles) of 3-dodecyn-1-ol in 35 ml. ofethyl acetate was added 0.300 g of Lindlar catalyst (Lindlar, HelveticaChimica Acta 35, 450 (1952)). The hydrogenation was carried out atatmospheric pressure with stirring. When the theoretical quantity ofhydrogen had been taken up, the hydrogenation was stopped and thereaction mixture was filtered through Celite. After removal of thesolvent, in vacuo, the residue was evaporatively distilled under reducedpressure to afford 2.95 g (91.6%) of (Z)-3-dodecen-1-ol as an oil.

EXAMPLE VIII

A 2.1 g (11.4 mmoles) sample of (Z)-3-dodecen-1-ol in 10 ml pyridine wastreated with 5.7 g (30 mmoles) of p-toluenesulfonyl chloride in 30 ml ofpyridine, at room temperature. After stirring for 5 hrs., the reactionmixture was diluted with ether and the product extracted. The ethereallayer was washed twice with 1 N H₂ SO₄, water, saturated NaHCO₃solution, water and dried over MgSO₄. The residue (3.2 g) obtained afterremoval of the solvent was chromatographed on silica gel. Hexane-ether9:1 eluted 2.4 g (62.2%) of the tosylate derivative. This material (7.1mmoles) was dissolved in 10 ml of acetone and slowly added to a solutionof 4.8 g (32 mmoles) of NaI in 55 ml of acetone. After stirring for 17hrs. at room temperature, most of the acetone was removed in vacuo. Theresidue was diluted with hexane. The organic layer was washed with 10%NaHSO.sub. 3 solution, twice with water, dried over MgSO₄ andconcentrated under reduced pressure. Evaporative distillation of theresidue produced 1.7 g (81.5%) of pure (Z)-1-iodo-3-dodecene as an oil.

EXAMPLE IX

A mixture of 0.43 g (1.46 mmoles) of (Z)-1-iodo-3-dodecene and 0.38 g(1.45 mmoles) of triphenylphosphine was heated at 90° C. for 3 hrs.under argon to produce 0.81 g of[(Z)-3-dodecen-1-yl]triphenylphosphonium iodide. This material was usedwithout further purification.

EXAMPLE X

Using the procedure of previous examples, (allZ)-7,7-dimethyl-5,8,11-eicosatrienoic acid was prepared in 54% yield.Thus 2.05 g (3.7 mmoles) of [(Z)-3-dodecenyl]-triphenylphosphoniumiodide was condensed with 0.5 g (2.5 mmoles) of(Z)-8-oxo-7,7-dimethyl-5-octenoic acid methyl ester (Wittig reactionconditions: THF/HMPT, 2:1, 2.0 ml of 1.6 M butyllithium in hexane; -78°C.) to yield 0.837 g (95%) of (all Z)-7,7-dimethyl-5,8,11-eicosatrienoicand methyl ester. Hydrolysis of this material with 0.1 ml of 5% aqueousKOH in 10 ml of methanol, followed by chromatographic purificationafforded 0.535 g (65%) of (all Z)-7,7-dimethyl-5,8,11-eicosatrienoicacid as an oil.

EXAMPLE XI Inhibition of the In Vitro Synthesis of SRS-A in RatPeritoneal Cells

To study the effect of drugs on SRS-A synthesis in rat peritoneal cells,these cells (including mast cells, monocytes, eosinophils andneutrophils) were isolated from male Sprague-Dawley rats (Charles RiverLaboratories) weighing 180-220 g by the lavage procedure described byHerzig, D. G. and Dusner, E. J. Journal of Pharmacology and ExperimentalTherapeutics, 194, 457-460 (1975) with the exception that Hanks balancedsalt solution used in these experiments was adjusted to pH 6.9 with 5%(V/V) of 0.1 M aqueous phosphate buffer and contained 50 mg/ml sodiumheparin. After removal from the peritoneal cavity of rats, the cellswere subsequently isolated by centrifugation at 400×gravity for 10minutes at 4° C. and resuspended to a concentration of about 2,000,000cells per ml in Hanks buffer.

Samples for evaluation were prepared by adding various concentrations oftest drugs to 2 ml aliquots of the resuspended cells in Hanks buffer.The 2 ml samples used for control contained 2 ml aliquots of resuspendedcells in Hanks buffer without drugs. All of the above samples (2 mlfinal volume) were preincubated at 37° C. for 10 minutes in the presenceof varying concentrations of test drug prior to challenge with 5×10⁷ Mionophore A23187. This ionophore is disclosed in Burka and Flower, Br.J. Pharmacology 65: 35-41 (1979). Antibiotic A23187 was used as a probefor the study of calcium and function in biological systems. Afterionophore challenge, SRS-A was synthesized in the samples by the cellsfor 10 minutes (at 37° C.) after which this synthesis was terminated byplacing the samples in a boiling water bath for 10 minutes followed bycentrifugation at 2,000×g (10 minutes) at 4° C. to remove coagulatedprotein and cellular debris. The SRS-A present in the resultingsupernatants was quantitated by a bioassay using a guinea pig ileum asdescribed in Orange, and Austen, Adv. Immunol, 10: 105-144 (1969). Forthis bioassay, a 1.5 cm segment of ileum was removed from animalsweighing 300 to 400 g and resuspended in an organ bath containing 10 mlof Tyrodes solution with 10⁻⁶ M atropine sulfate and 10⁻⁶ M pyrilaminemaleate. The bath was maintained at 37° C. and aereated with a mixtureof 95% O₂ and 5% CO₂. The concentration of SRS-A in the experimentalsamples was determined by a comparison of isotonic contraction responseselicited by the samples with those obtained with varying amounts of anSRS-A standard solution prepared from chopped guinea pig lung asdisclosed in Hitchcock, M. J. Pharmacol. Exp. Ther. 207: 630-640 (1978)and quantitated by the procedures of Orange, R. R. and Austen, K. F.Adv. Immunol. 10: 105-144 (1969) against histamine (1 unit of SRS-Abeing that amount which gives a contractie response similar to that of 5mg of histamine). In the absence of drug, the ionophore A23187-inducedSRS-A synthesis varied between 40 to 50 units of SRS-A per 10⁶ cells. Inthe presence of increasing concentrations of test drug, there was aconcentration-related decrease in SRS-A synthesis.

The mean percent inhibition ##EQU1## at each concentration of thevarious test drugs was calculated. The concentration of test drug whichinhibits the synthesis of SRS-A by 50% (IC₅₀) was determined for eachtest drug from a plot of the mean percent inhibition versus drugconcentration. Both the percent (%) inhibition at 10 μM and the IC₅₀ aregiven in the following table. The difference of units of SRS-A in thetest sample used in the fraction given above was obtained by subtractingthe units of SRS-A in the control from the actual measurement of theunits of SRS-A in the sample.

    ______________________________________                                                        % Inhibition                                                  Test Drug       at 10μ M   IC.sub.50 (μM)                               ______________________________________                                        (All Z)-7,7-Dimethyl-                                                                         100 ± 0(p<0.001)                                                                          1-3                                            5,8,11,14-eicosatetra-                                                        enoic acid                                                                    (All Z)-7,7-Dimethyl-                                                                         100 ± 0(p<0.001)                                                                         <10                                             5,8,11-eicosatrienoic                                                         acid                                                                          (Z,Z)-7,7-Dimethyl-                                                                           100 ± 0(p<0.001)                                                                         <10                                             5,8-eicosadienoic acid                                                        ______________________________________                                    

EXAMPLE XII

A 1.4 ml. portion of n-butyllithium (1.6 M solution in hexane) was addedto a solution of 1.4 g (2.74 mmol) of n-dodecyltriphenylphosphoniumbromide in 5.5 ml of 2:1 tetrahydrofuran-hexamethylphosphorictriamide,at -78° C., under argon. The solution turned orange-red in color. Tothis solution was then added 0.350 g (1.77 mmoles) of(Z)-8-oxo-7,7-dimethyl-5-octenoic acid methyl ester dissolved in 1 ml oftetrahydrofuran, using a syringe. The reaction mixture was stirred for30 minutes at -78° C. and an additional 45 minutes at 0° C. The productwas isolated by ether extraction using the conventional workup procedureand then chromatographed on silica gel. Hexane-ether (19:1) eluted 0.600g (97%) of (Z,Z)-7,7-dimethyl-5,8-eicosadienoic acid methyl ester. Thismaterial was dissolved in 6 ml of methanol and treated with 0.6 ml of 5%aqueous potassium hydroxide. After stirring at room temperature for 17hours, 3 ml of the methanol was evaporated in vacuo. The remainingsolution was acidified with oxalic acid and the product was extractedwith ether. The ether extracts were washed with brine, dried over MgSO₄and the solvent evaporated at reduced pressure. Purification of thecrude acid on a silica gel column provided 0.292 g (50.7%) of(Z,Z)-7,7-dimethyl-5,8-eicosadienoic acid (ca. 100% pure by GCanalysis).

EXAMPLE XIII Capsule Formulaton of (AllZ)-7,7-Dimethyl-5,8,11,14-eicostetraenoic acid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (All Z)-7,7-                                                                              0.1     0.5   5.0   10.0  25.0                                    Dimethyl                                                                      5,8,11,14-                                                                    eicostetraenoic                                                               acid                                                                     2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                         Procedures:                                                                   1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.           2. Mix with Items 4 and 5 and fill on capsule machine.                   

EXAMPLE XIV Tablet Formulation (Wet Granulation) of (allZ)-7,7-Dimethyl-5,8,11,14-eicosatetraenoic acid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (All Z)-7,7-                                                                              0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8,11,14-                                                                    eicosatetraenoic                                                              acid                                                                     2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized Starch                                                                     10.0    10.0  10.0  20.0  30.0                               5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1.5 in a suitable mixer, granulate with water. Dry, mill.        2. Mix with Item 5 and compress on a suitable press.                     

EXAMPLE XV Tablet Formulation (Direct Compression) of (AllZ)-7,7-Dimethyl-5,8,11,14-eicosatetraenoic acid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (All Z)-7,7-                                                                              0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8,11,14-                                                                    eicosatetraenoic                                                              acid                                                                     2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium   1.5     1.5   1.5   2.0   2.5                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.                       2. Add magnesium stearate (Item 5) as a premix and mix for 4 miuntes.         3. Compress on a suitable press.                                         

EXAMPLE XVI Capsule Formulations of (AllZ)-7,7-Dimethyl-5,8,11-eicosatrienoic acid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (All Z)-7,7-                                                                              0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8,11-                                                                       eicosatrienoic                                                                acid                                                                     2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                         Procedures:                                                                   1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.           2. Mix with Items 4 and 5 and fill on capsule machine.                   

EXAMPLE XVII Tablet Formulation (Direct Compression) of (AllZ)-7,7-Dimethyl-5,8,11-eicosatrienoic acid

    ______________________________________                                        Item Ingredients mg/tab1et                                                    ______________________________________                                        1    (All Z)-7,7-                                                                              0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8,11-                                                                       eicosatrienoic                                                                acid                                                                     2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium   1.5     1.5   1.5   2.0   2.5                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                         Procedures:                                                                   1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.                       2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.         3. Compress on a suitable press.                                         

EXAMPLE XVIII Tablet Formulation (Wet Granulation of (AllZ)-7,7-Dimethyl-5,8,11-eicosatrienoic acid methyl ester

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (All Z)-7,7-                                                                              0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8,11-                                                                       eicosatrienoic                                                                acid                                                                     2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                            10.0    10.0  10.0  20.0  30.0                                    Starch                                                                   5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.        2. Mix with Item 5 and compress on a suitable press.                     

EXAMPLE XIX Capsule Formulation of (Z,Z)-7,7-Dimethyl-5,8-eicosadienoicacid oxazole

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (Z,Z)-7,7-  0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8-                                                                          eicosadienoic                                                                 acid                                                                     2.   Lactose     183.5   183.9 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.           2. Mix with Items 4 and 5 and fill on capsule machine.                   

EXAMPLE XX Tablet Formulation (Direct Compression) of(Z,Z)-7,7-Dimethyl-5,8-eicosadienoic acid

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (2,2)-7,7-  0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8-                                                                          eicosadienoic                                                                 acid                                                                     2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium   1.5     1.5   1.5   2.0   2.5                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.                       2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.         3. Compress on a suitable press                                          

EXAMPLE XXI Tablet Formulation (Wet Granulation) of(Z,Z)-7,7-Dimethyl-5,8-eicosadienoic acid

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (Z,Z)-7,7-  0.1     0.5   5.0   10.0  25.0                                    Dimethyl-                                                                     5,8-                                                                          eicosadienoic                                                                 acid                                                                     2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                            10.0    10.0  10.0  20.0  30.0                                    Starch                                                                   5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.        2. Mix with Item 5 and compress on a suitable press.                     

EXAMPLE XXII Capsule Formulation (AllZ)-7-methyleicosa-5,8,11,14-tetraenoic acid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (All Z)-7-  0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8,11,14-                                                                    tetraenoic acid                                                          2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                         Procedures:                                                                   1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.           2. Mix with Items 4 and 5 and fill on capsule machine.                   

EXAMPLE XXIII Tablet Formulation (Wet Granulation) of (AllZ)-7-methyleicosa-5,8,11,14-tetraenoic acid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (All Z)-7-  0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8,11,14-                                                                    tetraenoic acid                                                          2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregaltinized                                                                             10.0    10.0  10.0  20.0  30.0                                    Starch                                                                   5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.        2. Mix with Item 5 and compress on a suitable press.                     

EXAMPLE XXIV Tablet Formulation (Direct Compression) of (AllZ)-7-methyleicosa-5,8,11,14 tetraenoic acid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (All Z)-7-  0.1     0.5   5.0   10.0  25.0                                    methyleicosa                                                                  5,8,11,14                                                                     tetraenoic acid                                                          2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium   1.5     1.5   1.5   2.0   2.5                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.                       2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.         3. Compress on a suitable press.                                         

EXAMPLE XXV Capsule Formulations of (AllZ)-7-methyleicosa-5,8,11-trienoic acid

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (All Z)-7-  0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8,11-                                                                       trienoic acid                                                            2.   Lactose     183.9   183.5 179.0 281.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                         Procedures:                                                                   1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.           2. Mix with Items 4 and 5 and fill on capsule machine                    

EXAMPLE XXVI Tablet Formulation (Direct Compression) of (AllZ)-7-methyleicosa-5,8,11-trienoic acid

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (All Z)-7-  0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8,11-                                                                       trienoic acid                                                            2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium   1.5     1.5   1.5   2.0   2.5                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.                       2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.         3. Compress on a suitable press.                                         

EXAMPLE XXVII Tablet Formulation (Wet Granulation) of (AllZ)-7-methyleicosa-5,8,11-trienoic acid

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (All Z)-7-  0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8,11-                                                                       trienoic acid                                                            2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                            10.0    10.0  10.0  20.0  30.0                                    Starch                                                                   5.   Magnesium   1.0     1.0   1.0   2.0   2.0                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry mill.         2. Mix with Item 5 and compress on a suitable press.                     

EXAMPLE XXVIII Capsule Formulation of (Z,Z)-7-methyleicosa-5,8-dienoicacid

    ______________________________________                                        Item Ingredients mg/capsule                                                   ______________________________________                                        1.   (Z,Z)-7-    0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8-dienoic acid                                                         2.   Lactose     183.9   183.5 179.0 218.0 257.0                              3.   Starch      30.0    30.0  30.0  50.0  70.0                               4.   Talc        5.0     5.0   5.0   10.0  15.0                               5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       220 mg  220 mg                                                                              220 mg                                                                              290 mg                                                                              370 mg                             ______________________________________                                         Procedures:                                                                   1. Mix Items 1-3 in a suitable mixer. Mill through a suitable mill.           2. Mix with Items 4 and 5 and fill on capsule machine.                   

EXAMPLE XXIX Tablet Formulation (Direct Compression) of(Z,Z)-7-methyleicosa-5,8-dienoic acid

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (Z,Z)-      0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8-dienoic acid                                                         2.   Lactose     85.4    85.5  81.0  103.0 112.5                              3.   Avicel      30.0    30.0  30.0  45.0  60.0                               4.   Modified Starch                                                                           8.0     7.5   7.5   10.0  15.0                               5.   Magnesium   1.5     1.5   1.5   2.0   2.0                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              170 mg                                                                              215 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer for 10-15 minutes.                       2. Add magnesium stearate (Item 5) as a premix and mix for 4 minutes.         3. Compress on a suitable press.                                         

EXAMPLE XXX Tablet Formulation (Wet Granulation) of(Z,Z)-7-methyleicosa-5,8-dienoic acid

    ______________________________________                                        Item Ingredients mg/tablet                                                    ______________________________________                                        1.   (Z,Z)-7-    0.1     0.5   5.0   10.0  25.0                                    methyleicosa-                                                                 5,8-dienoic acid                                                         2.   Lactose     103.9   103.5 99.0  148.0 197.0                              3.   Modified Starch                                                                           10.0    10.0  10.0  20.0  30.0                               4.   Pregelatinized                                                                            10.0    10.0  10.0  20.0  30.0                                    Starch                                                                   5.   Magnesium   1.0     1.0   1.0   2.0   3.0                                     Stearate                                                                      Total       125 mg  125 mg                                                                              125 mg                                                                              200 mg                                                                              285 mg                             ______________________________________                                         Procedure:                                                                    1. Mix Items 1-5 in a suitable mixer, granulate with water. Dry, mill.        2. Mix with Item 5 and compress on a suitable press.                     

What is claimed is:
 1. A compound of the formula: ##STR15## wherein Δdesignates a cis configuration, R is hydrogen or lower alkyl; and R₁ andR₂ are hydrogen or methyl with the proviso that where one of R₁ and R₂is hydrogen the other is methyl, and pharmaceutically acceptable saltsthereof where R is hydrogen.
 2. A compound according to claim 1 which is(Z,Z)-7,7-dimethyleicosa-5,8-dienoic acid.
 3. A compound according toclaim 1 which is (Z,Z)-7-methyleicosa-5,8-dienoic acid.